The connections of trigeminal sensory neurons with their peripheral targets are formed early in fetal development. An early step in the establishment of these connections is the growth and guidance of trigeminal sensory axons from their cell bodies of origin in the trigeminal ganglion to their target fields, but little is known about the mechanisms that direct this guidance. One mechanism that is thought to contribute to this guidance is long-range chemoattraction, or chemotropism. A previous study has shown that the epithelium of the developing maxillary and mandibular arches (both early targets of trigeminal sensory axons) secretes a chemoattractant factor that can selectively attract the axons in cell culture, and which is likely to contribute to guiding the axons to their targets in vivo. The attractant factor, termed "Maxillary Factor" (or MF), has not been identified. The long-term aim of this proposal is to understand the cellular events and molecular mechanisms used to guide the axons of trigeminal sensory neurons to their targets during development. The immediate aim is to characterize and to identify MF, and then to use this identification to determine its mechanism of action and its contribution to the establishment of neuronal connections in the trigeminal system. These studies will provide insight into the mechanisms that direct normal development of the trigeminal sensory system. The identification of MF will also be of more general significance, since to date only one family of axonal chemoattractants, the netrins, has been characterized at the molecular level. These studies will therefore provide additional insight into the types of molecules that function as target-derived chemoattractants in the developing nervous system, and their mechanisms of action. Defects in the initial establishment of neuronal connections may have devastating consequences on the eventual functioning of the nervous system, and may account for a variety of neurological disorders of childhood. Understanding the mechanisms involved in the normal establishment of connections, and the consequences of abnormal functioning of these mechanisms may therefore provide insight into some of these disorders and the means to treat them. In addition, since mechanisms that control axon growth during development are likely to be essential for axonal regeneration, this understanding is also fundamental to our ability to restore normal function following neural trauma in adults.